Cardiovascular

Question 1

Adrenoceptors (alphas)

Answer 1

a1
- In smooth muscle
- GqPCR
- Constriction of SM
=> Arterial vasoconstriction
=> Venous vasoconstriction
=> Mydriasis
=> GIT sphincter contraction
=> Pregnant uterus
- Glycogenolysis
- Gluconeogenesis

a2
- Throughout CNS
- GiPCR
- CNS
=> Sedation
=> ↓central SNS outflow
=> ↓MAC
- Spinal cord
=> Analgesia (modulate descending pain pathway)
- Platelet aggregation
- ↓Insulin release
- ↑Glucagon release
- ↓ADH release

Question 2

Adrenoceptors (Beta)

Answer 2

B1
- In heart, platelets, juxtaglomerular cells
- GsPCR
- Positive inotropic effect
- Positive chronotropic effect
- Platelet aggregation
- ↑Renin secretion
- Decr glucose uptake in white fat

B2
- In bronchi, heart, uterus, vascular SM
- GsPCR
- Relaxation of SM
- Glycogenolysis
- Gluconeogesis
- Incr insulin
- Tremour
- Thickened saliva
- ↓Histamine release from mast cells

B3
- In adipose tissues
- GsPCR
- Lipolysis and thermogenesis in brown and white adipose tissue

Question 3

Adrenoceptors (Dopamine)

Answer 3

D1-type (D1,5)
- In CNS + peripherally
- GsPCR
- Mimics B2 effect -> regional vascular dilation
- Motor function
- Cognitive function
- Cardiovascular function

D2- type (D2,3,4)
- In CNS, CTZ, peripherally
- GiPCR
- Pre-synaptic inhibit NA release from sympathetic terminals -> similar effect of ACh and a2-agonists
- Post-synaptic - mimic a1 and a2 vasoconstriction on blood vessels - action relatively weak
- ↓Prolactin release
- Motor function
- Behaviour

Question 4

Direct vs indirect activity

Answer 4

Direct
- Need OH group on C3 and/or OH group on Beta-carbon chain

Indirect
- Act by displacing NA from vesicles

Question 5

Potency + structure

Answer 5

• Higher potency with increased OH groups, i.e C3, C4, BC
• Reduced potency if lacking OH groups
  => Dobutamine lacks B-OH - mod potency
  => Ephedrine only has B-OH - low potency

Question 6

Metabolism

Answer 6

Catecholamines
- Metabolised bu both MAO and COMT

Synthetic non-catecholamines
- Lack OH group at C4
- Not metabolised by COMT (COMT need both -OH on C3 + C4)
- Metabolised only by MAO - slower metabolism, MAOi may exaggerate response

Question 7

Receptor selectivity

Answer 7

Alpha selectivity
- OH on C3 and BC
- Lack of 4-OH confers relative a1 selectivity

Beta selectivity
- N-substitution
- Longer chain on terminal amide confers B-selectivity (also prevent MAO activity)
- B2 selectivity - resorcinol ring
=> OH on C3 + C5 with long terminal amide substitution

Alpha + beta
- B-OH

Question 8

Inotropes

Answer 8

Agents that alter the force of myocardial contraction without affecting afterload and preload.

Catecholamines (B1 agonists)
- Naturally occurring - Adr, NA, dopamine
- Synthetic - isoprenaline, dobutamine, dopexamine

Phosphodiesterase inhibitors
- Non-selective - aminophylling
- Selective - milrinone, enoximone

Cardiac glycosides
- Digoxin

Other inotropic agents
- Glucagon, GsPCR -> adenylate cyclase -> incr CAMP -> incr intracellular Ca2+
- T3 + T4
- Ca2+ salts
- Ca sensitiser - Levosimenden - acutely decompensated CCF. Binds to cardiac troponin-C -> ↑sensitivity to Ca2+. Opens ATP-sensitive K+ channels -> vasodilation

Question 9

Inotropy MoA

Answer 9

Many different mechanisms - common endpoint is positively influencing interaction of Ca with actin and myosin in cardiac myocyte

B-agonist and PDEi ↑activity of PKA
- B-agonist -> ↑cAMP -> ↑PKA
- PDEi -> ↑cAMP -> inhibits MLCK -> promotes relaxation and vasodilation
- ↑PKA -> Ca channel phosphorylation ↑Ca channel opening
=> Activation of Ca-ATPase on SR - ↑Ca uptake in diastole + improved lusitropic function

Digitalis compounds
- Inhibit Na/K ATPase indirectly by ↑intracellular Ca by preventing Na/Ca exchange
- ↑cytosolic Na, decr activity of Na/Ca exchanger
- Indirectly ↑intracellular Ca by preventing removal from SR

Ca sensitiser (Levosimendan)
- Directly ↑Ca affinity for TropC at actin-myosin complex
- Prolongs systolic interaction between actin and myosin ↑force of contraction
- Binding dependent on cytosolic Ca concentration
- ↑inotropy without ↑myocardial O2 demand

Question 10

Vasopressors

Answer 10

Most exert vasoconstrictive actions via a1 receptor
- Exceptions is vasopressin - V1

Stimulation of a1 or V1 on vascular SM act via separate GqPCR to stimulate PLC -> hydrolyses PIP2 to generate IP3 + DAG
- IP# 3 -> ↑Ca release from SR
- DAG activated PKC -> ↑Ca influx via VGCC
- ↑cytosolic Ca -> ↑vascular SM tone

Question 11

Adrenaline

Answer 11

Catecholamine
- Methyl group at terminal amine enhances B
- 3, 4, and B-OH confers direct activity
- MAO and COMT substrate - no a-sub
Clinical use - anaphylaxis, systole, low CO states/ shock, local vasoconstriction
Brown vial to prevent light degradation
Made up in dextrose - prevent oxidative degradation
Dose
- 1:1000 = 1mg/mL
- 1:10,000 = 100mcg/mL
- Arrest = 1mg bolus
- Anaphylaxis = IV 100mcg, IM 500mcg
Administration - IV, IM, inhaled, nebuliser, SC (with LA)

MoA - Direct sympathomimetic with approx equal alpha and beta activity. Dose dependent effects.
- Low dose predominant B (B2>B1)
- Int dose B and a1 effects
- High dose predominant a1

PK
- A - ineffective PO because of inactivation, unpredictable tracheal absorption
- M
=> Neural - MAO metabolises within neurons from uptake-1, outer surface of mitochondria
=> Extra-neural - COMT - liver, kidneys, blood
=> Metabolites - metadrenaline, and vanillyl-mandelic acid (VMA)
- E - urine, T1/2B = 2mins

CNS
- Limited penetration but some excitatory effects
- ↑MAC
- ↑Pain threshold
- Little effect on CBF

CVS
- B effects - +ve inotropy (↑CO, ↑MO2 consumption), +ve chronotropy (↑HR and ↓O2 supply, can see reflex brady), ↓SVR (peripheral B2, seen more with lower dose infusions), coronary vasodilation, ↓threshold for arrhythmia
- A1 effects - ↑SVR + MAP (with higher/bolus dose)

RS
- Bronchodilation
- ↑PVR
- ↑MV (↑Vt + RR)

Metabolic
- ↑BMR
- ↑Glycogenolysis
- ↑Gluconeogenesis
- ↑Lipolysis
- ↑Glucagon secretion
- Initially ↑insulin secretion (B2), then ↓insulin secretion (a)

Renal
- ↓RBF 40%
- GFR stable
- ↓Bladder tone, ↑sphincter tone -> urinary retention
- ↑Renin

Other
- ↑Platelet aggregation
- ↓Intestinal tone and secretions -> ↑blood flow
- Inhibits contraction of pregnant uterus - relaxation, a1 vasoconstrion ↓uterine blood flow
- Lactic acidosis

Anaphylaxis
- Alpha - vasoconstriction of small arterioles and pre capillary sphincters ↑MAP and ↓mucosal oedema
- Beta - bronchodilation, stabilisation of mast cells ↓release of HA, tryptase, inflam markers

Question 12

Noradrenaline

Answer 12

Catecholamine
- No substitution on terminal amine confers a-selectivity
- Has some minor B effects
- No a-substitution confers MAO activity
Dose
- Titrate to response 1-30mcg/min (0.05-0.5mcg/kg/min) as an infusion
Incompatible with barbiturates and NaHCO3

MoA
- Direct and indirect sympathomimetic with predominant alpha effects
- Some B1 effects, no B2

PK
- A - significant first past metabolism, ineffective PO
- D- DoA 5mins, elimination rapid, receptor effect prolonged - 30mins, tachyphylaxis with prolonged administration. Does not cross BBB
- M
=> Uptake 1 - active uptake back into nerve terminal -> metabolised by MAO or recycled
=> Uptake 2 - diffusion away from nerve -> systemic circulation -> metabolised by COMT
=> Metabolites - normetadrenaline, vanillyl-mandelic acid (VMA)
- E - urine, pulm uptake (25%). T1/2B = 2mins

CNS
- ↓CBF and CMRO2
- Mydriasis

CVS
- ↑SVR + MAP (arterial vasoconstriction)
- ↑VR (venoconstriction)
- Reflex bradycardia
- May ↓CO
- Coronary vasodilation (↑blood flow)

RS
- ↑PVR (↑RV perfusion)
- ↑Vt, RR, MV
- Bronchodilation

Other
- ↓uterine blood flow (↑contractility of pregnant uterus - fetal hypoxia and bradycardia)
- ↓hepatic and splanchnic blood flow
- ↓RBF but GFR maintained
- ↑urinary sphincter tone

Question 13

Metaraminol

Answer 13

Synthetic sympathomimetic amine
- Non-catecholamine (lack OH at C4)
OH on B-carbon - direct, alpha
- No 4-OH and N substitution makes it a1 selective, also uptake 1 substrate as primary amine
- CH3 substitution on a-carbon - indirect, MAO resistant
Smaller amine, a>B
Dose - bolus 0.5-1mg, infusion 1-10mg/hr

MoA
- Direct and indirect sympathomimetic action
- Mainly a1 agonist
- Minimal B activity
- Some uptake of metaraminol into adrenergic nerve endings -> released as NT
- Triggers NA release from vesicles - tachyphylaxis occurs as NA is depleted, additionally causes some adrenaline release

PK
- Unclear/ limited data
- Onset within 1-2mins, duration 10-20mins
- 45% protein bound
- Des not cross BBB
- M - non-catecholamine - resistant to COMT
=> Resistant to MAO due to methyl group at a-carbon
- E - T1/2 6hrs

CNS
- ↓CBF

CVS
- ↑SVR + MAP (arterial vasoconstriction)
- Reflex brady
- Indirectly ↑coronary blood flow
- ↑PVR
- Minor inotropic action, but CO may fall due to ↑afterload

Renal
- ↓RBF

Other
- Contraction of pregnant uterus and ↓UBF
- ↑glycogenolysis
- Inhibits insulin release -> ↑BSL
- ↑lipolysis -> ↑FFA
- ↑BMR and ↑temp

Toxicity
- Overdose with hypertensive crisis may precipitate LV failure
- Extravascular injection may cause tissue necrosis

Question 14

Ephedrine

Answer 14

Non-catecholamine sympathomimetic amin
- Four isomers, only L- isomer active
Lack of hydroxylation ↓ability to stimulate directly adrenergic receptors - predominantly indirect action(uptake 1 substrate), also ↑lipid solubility (may have CNS effects)
Methyl group on a-carbon block oxidation by MAO and prolongs its action. Not COMT substrate as non-catecholamine
Dose 3-6mg bolus

MoA
- Direct and indirect action
- Mixed a + B agonist (predominantly B, direct action)
- ↑NA release from nerve endings (predominantly a-activity, indirect)
- Competes with NA for reuptake into nerve terminals via uptake 1 ↑NA in synapse
- Tachyphylaxis due to depletion of NA stores

PK
- A - rapid and complete PO absorption
- D - large Vd with distribution to all major organs, crosses BBB
- M - not metabolised by MAO or COMT, largely resists metabolism and is excreted in the urine.
=> Hepatic metabolism - small amount N-demethylated to norephedrine - may produce central stimulant effects
=> Longer DoA 10-60mins
- E - >50% unchanged in urine, urinary excretion is pH dependent and enhanced in acidic urine, renal disease impairs elimination. T1/2 3-6hrs.

Drug interactions
- ↑MAC
- MAOi/ TCA ↑effect -> HTN crisis
- Clonidine enhances pressor effect

CNS
- CNS stimulant similar to amphetamine (agitation and insomnia as it crosses BBB)
- ↑CBF and CMRO2

CVS
- ↑CO (+ve inotrope) -> ↑myocardial work + O2 consumption
- ↑HR (direct effect)
- ↑BP
- ↑CBF
- Arrhythmogenic - ↑myocardial irritability
- ↑PAP
- May ↑circulating volume due to post capillary venoconstriction

RS
- Stimulant - ↑RR + Vt
- Bronchodilator

Other
- ↓RBF + ↓GFR
- Contracts urinary sphincter and relaxes detrusor - urinary retention
- ↓uterine tone and does not constrict uterine vessels
- Mydriasis
- Relaxes GIT and causes splanchnic vasoconstriction

Question 15

Phenylephrine

Answer 15

Synthetic sympathomimetic amine
Non-catecholamine with direct activity
- ↑alpha activity, no B
- N-methyl substation only and no a-substituion means MAP substrate
- Non-catecholamine so not COMT substrate
Dose - 50-100mcg boluses, 20-200mcg/min infusion. Requires dilution from 10mg/ml solution to 100mcg/ml solution (in 100ml bag)

MoA
- Direct a1 agonist with no B effects
- Minimal a2 effects

PK
- D - rapid onset, DoA 10mins (longer than NA)
- M - hepatic metabolism by MAO
- E - renal, mainly as metabolites. T1/2B 2-3hrs

Drug interactions
- MAOi/TCA

CVS
- ↑SVR + MAP (vasoconstriction)
- Reflex brady may ↓CO
- Indirectly ↑CBF
- Not arrhythmogenic
- ↑PVR

Other
- Mydriasis (a1 stimulation)
- ↓RBF
- ↓Uterine blood flow
- May cause urinary retention
- Extravasation -> tissue necrosis
- Topical nasal congestant
- With LV dysfunction, combination of ↓HR and ↑afterload can significantly ↓CO

Question 16

Vasopressin

Answer 16

Nonapeptide hormone
- Sequence of 9 amino acids
- No structural similarity to other sympathomimetics
Endogenous - synthesised in supraoptic and paraventricular nuclei in hypothalamus
Exogenous - 3 forms - argipressin (vasoactive), terlipressin, desmopressin
=> Desmopressin has 10x ADH action but 1500x less vasoconstriction

Clinical uses
- Vasodilatory refractory shock
- DI
- Bleeding varices
- VF arrest (in place of adrenaline)

Dose = 20IU = 400mcg argipressin (20units/mL) - infusion 0.6-2.4 units/hr

MoA
- ADH and V2 Gs receptor in basolateral membrane of renal tubule - activates adenylyl cyclase -> ↑cAMP -> ↑formation of vesicles containing aquaporin-2, aquaporin-2 inserted into apical membrane ↑permeability to H2O -> H2O reabsorption in CD
- Vasoconstriction via V1 GqPCR

PK
- A - extremely low PO bioavailability due to intestinal proteases
- M - by specific vasopressinases in the liver and kidney
- E - 65% unchanged in urine, T1/2 = 15mins

Drug interactions
- Potentiation of its antidiuretic effect can be seen with carbamazepine, chlorpropamide, clofibrate, fludrocort, TCAs
- Inhibition of antidiuretic effect with NA, lithium, heparin, alcohol

CVS
- ↑SVR + MAP in septic shock (vasoconstriction)
- Coronary vasoconstriction even with small doses

Renal
- ↑Water reabsorption in CD
- ↑Na reabsorption and K secretion by CCD
- ↓Renin secretion

Other
- ↑Peristalsis - N+V, abdo pain
- Allergy
- V3 (aka V1b) is a G1GPCR in ant pituitary -> ACTH/ prolactin release
- Acts on endothelium to ↑release of VWF

Question 17

Isoprenaline

Answer 17

Synthetic catecholamine with direct activity
Isopropyl group on terminal amine - B activity with no alpha, no MAO activity

Clinical uses - refractory bradycardia
Dose - 0.01-0.2mcg/kg/min

MoA
- Selective B agonist

PK
- Metabolised predominantly via COMT in liver to sulphur conjugates
- 15-75% eliminated unchanged in urine, remainder as conjugates
- T1/2 = 5mins

CNS
- Stimulant

CVS
- Powerful inotrope and chronotrope
- ↑CO + SBP
- B2 action may ↓SVR -> ↓DBP
- ↑myocardial demand + ↓O2 supply (↑HR + ↓DBP)

RS
- Potent bronchodilator

Other
- Metabolic effects similar to adrenaline
- Inhibits HA release

Question 18

Dobutamine

Answer 18

Synthetic catecholamine (isoprenaline derivative)
- Large substitution on terminal amine give B selectivity
- Lack 5-OH so no B2
- Not an uptake 1 substrate
- Not a MAO substrate - a-unsubstituted but bulky N-substitution
Has 2 isomers - both isomers have B1 agonist effects. L-isomer has a1 agonist effects and R-isomer has a1 antagonist effect

Clinical uses - stress echo, low CO state, CCF
Dose = 2-20mcg/kg/min

MoA
- Direct selective B agonist
- Predominant B1, some B2

PK
- M - metabolised by COMT, conjugated to a glucuronide and excreted
- E - predominantly urine, 20% faeces, T1/2 2mins

CVS
- ↑inotropy, chronotopy
- Small ↓in SVR via B2
- ↑UO secondary to CO - no specific renal effect

Question 19

Milrinone

Answer 19

Bipyridine methyl carbonitrile derivative of amrinone
Clinical uses - short term management of low CO state associated with cardiac surgery
Good PO BA 92%
Dose - 50mcg/kg infusion loading over 10mins, 0.125-0.75mcg/kg/min

MoA
- Selective PDE-III inhibitor within myocardium and vascular SM
- ↑cAMP -> ↑Ca in myocardium and improves Ca reuptake -> +ve inotropy and lusitropy
=> Inhibits MLCK in SM -> vasodilation - systemic and pulmonary
- Inodilator
=> Positive inotropic effects -> ↑CO
=> Vasodilatory effects -> ↓SVR + PVR

PK
- M - largely resists metabolism, 12% undergoes hepatic metabolism via glucuronidation
- E - excreted in urine unchanged (80%), T1/2 2.3hrs, prolonges in renal impairment

CVS
- Positive inotrope -↑CO, improves LV lusitropy
- ↓SVR - vasodilator, preserves myocardial O2 balance
- Little effect on HR and BP
- May need vasopressor if BP falls
- ↓PVR - pulm vasodilation may lead to ↑V/Q mismatch

Other
- Anti-ischaemic -reduced platelet aggregation, coronary vasodilation
- No tachyphylaxis

Toxicity
- Ventricular ectopics/ arrhythmias - ↑risk of AF (incr myocardial Ca)
- Hypotension
- ↑mortality with chronic use (↑myocardial Ca -> ↑energy consumption -> arrhythmogenesis), may cause localised ischaemia due to ↑demand

Question 20

Aminophylline

Answer 20

Non-selective PDEi
Methyl-xanthine derivative
Complex of 80% theophylline + 20% solubilising agent

MoA
- Non-selective PDEi -> ↓degradation cAMP -> ↑intracellular cAMP
- Non-selective adenosine receptor antagonist -> inhibits degranulation of mast cells

PK
- A - high PO bioavailability
- D - protein binding 50%
- M - hepatic metabolism via CYP to inactive metabolites, low hepatic ER - enzyme inhibitors reduce elimination, enzyme inducers increase elimination
- E- 10% excreted unchanged in urine, T1/2 6hrs

CVS
- Mild +ve inotropy + chronotropy
- ↑arrhythmias (reduced threshold)

RS
- Bronchodilation
- ↑sensitivity of resp centre to CO2
- ↑contractility of diaphragm

Other
- ↓seizure threshold
- Weak diuretic effect due to natriuretic effect (inhibits tubular Na reabsorption) and can be physically addictive (caffeine)
- ↑BSL due to SNS activations

TI - narrow
- Saturable metabolic pathways and may convert to zero order kinetics and accumulate
- Therapeutic Cp 10-20mcg/ml
- Toxic Cp >35mcg/ml

Question 21

Dopamine

Answer 21

Catecholamine
- DA, a1, B1 agonist
- 3, 4-OH
- Primary amine so uptake 1 substrate
- No a-substitution so MAO activity

Clinical uses - low CO states, shock, impending ARF (diuresis)
Dose - 1-20mcg/kg/min

MoA
- DA, a1, B1 agonist
- Lower doses acts as D1/D2, higher doses acts at B and then alpha
- Low dose acts primarily on the D1 receptor in renal, mesenteric and coronary vasculature (produces vasodilation with a resultant increase in GFR, RBF, Na excretion and UO)

PK
- Acts within 5mins, DoA 10mins
- M - approx 25% of dopamine converted to NA in adrenergic nerve terminals, then taken up
=> Metabolised by MAO + COMT
=> Inactive metabolites - 3-methoxy-4-hydroxy-phenyl-ethanol, NA metabolic products
- E - renal elimination of metabolites. T1/2 3mins

Drug interactions
- Dose reduced with MAOi
- Inactivated by alkaline solutions
- Phenothiazines block action (DA antagonists)

CNS
- Dopamine cannot cross BBB
=> DOPA can
- ↓Prolactin secretion
- Nausea

CVS
- <10mcg/kg/min -> B effects predominate
=> ↑contractility -> ↑CO
=> ↑HR
=> Coronary vasodilation
- >10mcg/kg/min -> a effects predominate
=> ↑SVR
=> VR
- ↑risk of arrhythmias vs NA

RS
- ↑PVR

Renal
- Indirect effects - ↑CO which ↑RBF + GFR
- Tubules - diuresis + natriuresis (D1)
- Renal vasodilation - ↑RBF + O2 supply whilst ↓O2 demand

Splanchnic effects
- Mesenteric vasodilation (D1 effect)

Question 22

Levosimendan

Answer 22

Calcium sensitiser
- ↑sensitivity of heart to Ca -> ↑contractility without a rise in intracellular Ca
- +ve inotropic effect by ↑Ca sensitivity of myocytes by binding to cardiac troponin C in a Ca-dependent manner
- Vasodilatory effects, by opening Katp channels in vascular SM to cause SM relaxation
- Combined inotropic + vasodilatory action -> ↑force of contraction, ↓preload + ↓afterload
- By opening mitochondrial Katp channels in cardiomyocytes - cardioprotective effect

↑contractility without ↑O2 consumption

Question 23

Catecholamine refractoriness

Answer 23

• Prolonged exposure to agonists results in tachyphylaxis and tolerance - ↓response for given dose

Rapid
- Receptor phosphorylation by G-protein kinases and signalling kinases (PKA, PKC)
- ↓Gs activity, ↑Gi activity
- Uncoupling of G protein and receptor
- Receptor internalisation
- Activation of PDE reducing cAMP activity

Slower
- Receptor endocytosis

Question 24

Anticholinergics

Answer 24

Naturally occurring (tertiary amines)
- Atropine - tropic acid + tropine
- Hyoscine - tropic acid + scopine

Synthetic (quaternary amines)
- Glycopyrrolate - mandolin acid + tropine

MoA
- Muscarinic ACh receptor antagonists
=> Competitive
=> Reversible
=> Central activity (only tertiary amines cross BBB)
=> Peripheral activity (both tertiary and quaternary)
- Little effect on nicotinic Ach receptors - except at high doses of atropine

Effects

CNS (atrop + hyo only, glyco has NO CNS effect as doesn’t cross BBB)
- Central anticholinergic syndrome - restlessness, agitation, disorientation, hyperactivity, hyperthermia
- Mydriasis
- Sedation
- Amnesia
- Antiemetic

CVS
- Atrop/ glycol - initial brady (partial agonist at cardiac MAChR)
- All - tachycardia

RS
- Bronchodilation
- ↓Bronchial secretions

GIT/ GU
- Antisalagogue
- ↓LOS tone
- ↓Gastric acid secretion
- ↓GIT motility
- SM relaxation -> urinary retention in males

Other
- Atropine - anhidrosis (↓sweating) -> hyperthermia in children

Question 25

Atropine

Answer 25

Anticholinergic
Naturally occurring tertiary amine
Ester of tropic acid + tropine
Racemic mixture - only L-isomer active
Dose - 200-600mcg bolus, 3mg needed for total vagal blockade

PK
- A - <25 PO bioavailability
- D - 50% protein bound - crosses placenta and BBB. TTPE 204mins, Duration 30-60mins
- M - extensive metabolism by hepatic and tissue esterases, hydrolysed to tropic + tropic acid
- E - renal excretion of metabolites, minimal unchanged. T1/2 = 150mins

Question 26

Glycopyrrolate

Answer 26

Anticholinergic
Synthetic quaternary amine
Mandelic acid + tropine
No isomerism
Dose - 200-400mcg, 2.5mg neostigmine/500mcg glyco
Physically incompatible with thio, diaz

PK
- A - PO bioavailability <5%
- D - onset 3-9mins, rapid redistribution with 95% leaving plasma after 5mins, duration - antivagal for 3hrs, antisialagogue for 6hrs
- M - minimal metabolism
- E - 85% excreted unchanged in urine. T1/2 75mins

Question 27

Hyoscine

Answer 27

Anticholinergic
Naturally occurring tertiary amine
Ester of tropic acid + scopine
Racemic mixture - only L-isomer active
Hyoscine butyl bromide (buscopan) - does not cross BBB, does not cause sedation or central anti-emetic effects
Hyoscine hydro-bromide (scopolamine) - crosses BBB

Uses - antispasmodic, motion sickness
Dose - butylbromide 10-20mg

PK
- A - scopolamine used as transdermal patch, PO bioavailability 10%, well absorbed SC or IM
- D - faster onset than atropine, DoA 2hrs
- M - extensive metabolism by hepatic esterases and in tissues, metabolised to scopine + tropic acid
- E - renal excretion of metabolites, T1/2 2.5hrs

Question 28

Alpha antagonists

Answer 28

Non selective a1 + a2 antagonists- phentolamine + phenyxoybenzamine

Phentolamine
- a1 >a2 (3:1)
- Used for pheochromocytoma
- 10mg/ml (dilute in 20ml = 0.5mg/ml) - 1ml bolus
- Onset 1-2mins, DoA 5-20mins
- Hepatic metabolism
- Essential anti-metaraminol
- a1 - arterial vasodilation (↓SVR + BP), ↓PVR
- a2 - presynaptic ↑NA, ↑HR
- ↑CO - reflex tachycardia + ↑contractility triggered by baroreceptor reflex to ↓BP (a1)
=> ↑central SNS outflow, ↑NA release (a2)

Phenoxybenzamine
- Irreversible a blocker (a1 > a2) - covalent bond
- Used for phaeochromocytoma
- Long acting
- Inhibition of presynaptic reuptake of NA
- Corrects HTN and vasoconstriction
- Reduces intravascular volume deficit
- May cause sedation

Selective antagonists
a1 - Prazosin
a2 - Yohimbine

Prazosin
- Used for HTN, BPH, Raynaud’s
- Arterial vasodilation and venodilation -> ↓SVR -> ↓BP. ↓Preload
- 1st dose postural hypotension
- Relaxes prostate and ureteric SM -> Improves urine flow
- Hepatic metabolism, T1/2 7hrs
- Dose 0.5-5mg

Yohimbine
- Used for impotence
- Adverse effects - tachycardia, HTN, insomnia, anxiety, hallucinations

Question 29

Alpha 2 agonists

Answer 29

Phenylethylamines - a-methyldopa, NA
Imidazolines - clonidine, moxonidine, dexmed

Receptor subtypes
- a2a - mediates sedation, hypnosis, analgesis, neuroprotection, sympatholysis
=> Gi protein associated - ↓cAMP
- a2b - mediates vasoconstriction, anti-shivering, analgesia
- a2c - learning, stress response

Question 30

B-blockers MoA + classification

Answer 30

MoA
- Antagonise B adrenergic receptor - GsPCR -> ↓cAMP -> ↓PKA activation -> ↓phosphorylation of intracellular targets
- Cardiac pacemaker cells - ↓HCN channel activation -> ↓slope phase 4 -> ↓HR
- Ventricular myocyte -> ↓phosphyrolation of
=> Membrane L-Ca and SR ryanodine sensitive Ca channel (↓Ca influx)
=> Myosin (↓rate at which x-bridge cycling occurs)
=> Trop I and phospholamban (↓relaxation rate)

Classification - receptor selectivity
- Non-selective for B1 + B2 - propranolol, timolol, sotalol, carvedilol
- Cardio-selective for B1 - metoprolol, atenolol, esmolol
- Mixed a + B - labetalol (B non-selective, a1 selective, B&raquo_space;a1)

Classification - intrinsic sympathomimetic
- Partial B agonist activity = intrinsic sympathomimetic activity. Submaximal response despite maximal occupancy of B receptors. Low level circulating catecholamines -> agonist effects. High levels -> antagonist
- Present - Pindolol, acebutolol, timolol, labetalol at B2
- Absent - propranolol, metoprolol, atenolol, esmolol, sotalol

Lipid solubility
- High (cross BBB) - propranolol, metoprolol, labetalol, carvedilol, timolol, pindolol
- Low (doesn’t cross BBB) - esmolol, atenolol

Question 31

B-blockers effects

Answer 31

CNS
- More lipid soluble BB (propranolol, metoprolol)
=> Hallucinations, depression, nightmares
- MAC-sparing effects
- Mask effect of inadequate anaesthesia
- ↓IOP (↓production of aqueous humour)

CVS
- Negative inotropic effect (↓myocardial O2 demand)
- Negative chronotropic ( ↓SAN automaticity, ↓AVN conductivity, ↓HR, AV block, ↑myocardial O2 supply)
- Class II anti-arrhythmic
- ↓BP
- Rebound HTN after abrupt discontinuation
- May precipitate acute cardiac failure
- Exacerbation of PVD (B2)
- Exacerbation of Raynaud’s (B2)
- ↓HTN response to intubation + extubation
- Cardioprotective - ↓stress on atherosclerotic plaques, ↓cardiac cell apoptosis and necrosis, ↓plt aggregation, ↓B-receptor down regulation

RS
- Bronchospasm (B2) - caution in asthma

Metabolic
- Glucose - interference with glycogenolysis, obtund normal blood sugar response to ↓BSL, mask sx of ↓BSL
- Lipids - ↑triglycerides, ↓HDL
- ↓Renin release at juxtaglomerular apparatus (B1) -> ↓AT-II and its effects
- Hyperkalaemia

GIT
- Dry mouth

Other
- Esmolol - vein irritation and tissue necrosis after extravasation

Caution in
- Severe LV failure
- AV conduction delay
- Asthma, COPD
- Diabetes
- PVD - reflex vasoconstriction

Question 32

Metoprolol

Answer 32

Racemic mixture
Dose 1-2mg Q2-5mins

PK
- A - >95% PO absorption, but only 50% bioavailable
- D - IV onset 1-2mins, duration 5-8hrs. High lipid solubility - high lipid solubility, crosses BBB and breast milk. 15% protein bound, VD 5.5L/kg
- M - hepatic -> alpha-hydroxymetorprolol (10% activity). CYP2D6 O-demethylation > CYP3A4. CYP2D6 polymorphism (i.e slow metabolisers)
- E - renal excretion as metabolites, T1/2 3-7hrs

PD
- Selective B1 (cardiac)
- No intrinsic sympathomimetic activity
- Weak membrane stability activity

Question 33

Esmolol

Answer 33

10mg/ml solution
Dose 0.5mg/kg bolus, infusion 50-150mcg/kg/min

PK
- D - onset 6-10mins, offset 20mins, 55% protein bound, VD 3.5L/kg. High lipid solubility. Crosses placenta poorly.
- M - hydrolysis by red cell esterases to methanol and a primary acid metabolite (metabolite has minimal weak B antagonist activity)
- E - 70-80% in urine as metabolite, T1/2 10mins

PD
- Selective B1 (cardiac), at high doses may have B2
- Obtunds CVS response to intubation and sternotomy

Question 34

Labetalol

Answer 34

Mixture of 4 isomer
- R-R isomer has B activity
- S-isomer has a activity

PK
- A - 70% PO absorption, with 25% bioavailability, significant first pass metabolism
- D - highly lipid soluble, crosses BBB. 50% protein bound, variable VD 2-15L/kg
- M - extensively metabolised in liver to inactive conjugates
- E - renal excretion of metabolites. T1/2 3-8hrs

PD
- Mixed a + B antagonist (a1, B1, B2)- has intrinsic sympathomimetic activity at B2 (may cause vasodilation at vascular SM directly), ↓SVR
- B-non selective
- B»a (7:1 IV, 3:1 PO)
- Safe in pregnancy
- Alpha adverse reactions more common than B - nasal congestion, dizziness

Question 35

Propranolol

Answer 35

Racemic mixture
- S-isomer responsible for most effects
- R-isomer prevents peripheral conversion of T4 to T3
Dose = 1-2mg bolus Q2mina

PK
- A - >90% absorbed, with 30% bioavailability
- D - High lipid solubility. 90% protein bound, VD 3.5L/kg
- M - hepatic oxidative deamination then dealkylation or glucuronidation. Active 4-OH metabolite
- E - Renal elimination, T1/2 3-5hrs

PD
- Non-selective B1 + B2 - also timolol

Question 36

Sotalol

Answer 36

Non-selective blocker
Class II + III antiarrhythmic- blocks B-receptors and K+ ↑refractory period
Racemic mixture; L - class II + III, D - class III
Dose - PO 160-320mg, IV 0.5-1.5mg/kg

A - PO bioavailability 75-90%
D - Low lipid solubility
M - not metabolised
E - renal excretion, T1/2 12hrs

S/E
- B-blocker effects
- Torsade de point - ↑risk with high dose, bradycardia, antiarrhythmics, low Mg + K

Question 37

ACE inhibitors

Answer 37

Classification
- Sulfhydryl-containing - captopril
- Dicarboxylate-containing - enalapril, ramipril, perindopril, lisinopril
- Phosphate-containing - fosinopril

Indications - HTN, IHD, CCF

MoA
- Competitive ACE inhibitor -> ↓conversion of AT-I to AT-II -> ↓effects of AT-II
- ↓Breakdown of bradykinin

CVS
- Arterial vasodilation - ↓SVR + BP (CO may ↑ due to ↓after load)
- HR and baroreceptor reflex unaffected

Renal
- If poor renal perfusion (renal artery stenosis, hypovolaemia) - impaired efferent arteriole vasoconstriction, ↓GFR, renal impairment
- Hyeprkalaeima (↓aldosterone release)
- ↑RBF and may cause natriuresis

Other
- Dry cough - bradykinin mediated
- Angioedema
- Agranulocytosis and thrombocytopenia
- Rash
- Hypotension, dizziness, fatigue, GI upset
- 1st dose hypotension

Anaesthesia
- Hypotensive effect additive
- ↑Intra and post-op hypotension if not withheld
- ↑risk of renal failure/ AKI due to hypo perfusion under anaesthesia - esp if concomitant use of NSAIDs

Question 38

Angiotensin-II receptor blocker (ARB)

Answer 38

E.g losartan, candesartan
Indications - HTN, IHD, CCF

MoA
- Specific ATII (AT1) receptor antagonist
- Does not block AT2 and ACE
- Does not ↑bradykinin level

Effects
- Similar to those of ACEi
- No dry cough
- No angioedema

Angiotensin II
- MoA - two subtype of AT-II receptors (GPCRs)
=> AT1 + AT2
=> AT-II has greater affinity for AT1 receptors

Effects
- Potent vasoconstriction
- ↑ADH
- ↑Aldosterone
- ↑Thirst
- ↓Renin
- ↓GFR

Question 39

Hydralazine

Answer 39

Dose 5-10mg Q5min to effect- adult dose 20-40mg IV

MoA
- Direct action on vascular SM
=> Hyperpolarisation via opening of K channels
=> ↓intracellular Ca in vascular SM via inhibition of IP3
=> Activation of guanylate cyclase via NO

PK
- A - bioavailability ~15-30%
- D - onset within 15mins, highly protein bound, high VD 4L/kg, crosses placenta -> fatal tachycardia
- M - acetylation and oxidation with subsequent conjugation. Genetic polymorphisms -> fast and slow acetylators
- E - 50-90% excreted in urine, T1/2 1-3hrs

CVS
- ↓SVR - arterial vasodilation
- ↑CO due to ↓after load
- Reflex tachycardia - can be used with B-blockers to prevent
- ↑CBF
- ↑RBF secondary to CO

Other
- N+V
- Oedema due to Na retention and ↓UO
- ↑Plasma renin
- SLE-like syndrome with high doses - higher in females - typically with chronic use in slow acetylators
- Peripheral neuropathy/ blood dyscrasia - rare

Question 40

Calcium channel blockers

Answer 40

Classification
- Phenyl-alkylamines - verapamil
- Dihydropyridine - nifedipine, amlodipine, nimodipine
- Benzo-thiapines - diltiazem

Indications - HTN, IHD, Raynaud’s, SVT/AF/ Aflutter, tocolysis

MoA
- Competitive voltage gated L-type Ca2+ channel antagonism -> ↓Ca influx -> ↓intracellular Ca -> ↓SAN automaticity, ↓AVN conductivity, vasodilation, some negative inotropic effect

PK
- Well absorbed but limit bioavailability
- Lipid soluble, high VD (2-4L/kg), high protein binding
- High hepatic metabolism with relatively short T1/2

CNS
- Arterial vasodilation -> ↓SVR + BP, ↑CO (due to ↑HR + ↓afterload), ↑coronary BF, ↑cerebral BF -> ↑ICP -> headache
- Min venous vasodilation
- Reflex tachycardia
- ↓myocardial contractility -> may precipitate cardiac failure

RS
- ↓HPV

Other
- Tocolysis
- Peripheral oedema

Drug interaction
- May potentiate effect of NDMR
- Additive negative inotropic effects with volatiles -> profound drop in CO (incr risk of sinus pause, ↓MAC)
- Dantrolene and verapamil -> hyperkalaemia

Question 41

Nitric Oxide (NO)

Answer 41

Inorganic gas
Used as selective pulm vasodilator in pulm HTN

MoA
- Produced in vivo by NO synthase from L-arginine and O2 - requires NADP
- cGMP - diffuses to vascular SM layer and stimulates guanylate cyclase, ↑cGMP which activates a phosphorylation cascade -> SM relaxation + vasodilation. May also activate K channels hyperpolarising cell and ↓Ca entry

PK
- A - inhalation route (5-20ppm dose), continuous flow system ↓bolus effect (also minimises NO2 formation - ↓time for NO + O2 to mix)
- M - NO combines with oxyHb that is 60-100% saturated producing MetHb and nitrate; readily reacts with metal ions (Fe2+) in proteins and enzymes. Reacts with harm moiety in guanylate cyclase to ↑cGMP.
- During first 8hrs of admin MetHb ↑
- E- T1/2 <5s, nitrate eliminate via urine

CNS
- ↑CBF and may act as NT within ANS + CNS - role in learning, memory, analgesia, may ↑MAC

CVS
- Potent vasodilation - inhalation ensures selective pulm vasodilation due to rapid metabolism (avidly binds Hb and is inactivated prior to reaching systemic)
- Inhibits platelet aggregation - anti-thrombotic
- Anti-atherogenic - ↓proliferation of SM, expression of adhesion molecules, permeability to lipoproteins

RS
- Improves V/Q matching
- Abrupt cessation -> hyperaemia due to down regulation of endogenous production

Immune
- Macrophages use it to inhibit bacterial Fe-containing enzymes -> cell lysis
- Role in COX-2 activation and PG production

Toxicity
- MetHb - ↓O2 carrying capacity
- ↓platelet aggregation and adhesion -> bleeding
- Formation of NO2 if high O2 -> pulm toxicity, oedema, pneumonitis

Question 42

Sodium nitroprusside

Answer 42

Light brown solution when reconstituted with 5% dextrose
- Dark brown after exposure to light - liberation of cyanide ion (light sensitive breakdown)
- Fe2+ surrounded by 5xCN- and 1x NO

Clinical use - HTN crisis, LV failure
Dose - 0.5-6mcg/kg/min titrated to response

MoA
- Interacts with sulfhydryl groups in SM cell membrane stabilising membrane and preventing Ca influx
- Mediates effects via NO
=> Reacts with oxyHb to form NO, metHb and 5 CN-
=> Tolerance does not occur but MetHb does
=> Activates guanylate cyclase ↑cGMP and ↓intracellular Ca -> vasodilation

A - Not absorbed from GIT
D - onset immediate, TTPE 1-2mins, DoA 1-10mins. Confined to plasma + ECF
M - reacts with oxyHb in RBC to form NO, 5CN-, MetHb (MetHb + CN- -> cyano-metHb). Remaining cyanide converted in liver and kidneys to thiocyanate (100x less toxic than CN-, mostly excreted in urine)
E - T1/2 2mins, thiocyanate T1/2 2 days

CVS
- Arterial vasodilation - equal arterial + venous
=> ↓SVR + BP
=> ↑CBF + ICP - may cause steal phenomenon
=> ↓wall tension
=> Reflex ↑ renin release
- Venodilation - ↓VR -> ↓preload
- ↓Myocardial O2 consumption due to ↓preload and afterload
- Reflex tachycardia
- ↑CO in failing heart (↓preload + ↓afterload)

RS
- ↓HPV -> ↑shunt
=> ↓PaO2
- ↓PVR

Other
- MetHb
- ↓LOS tone
- May cause ileus
- Metabolic acidosis may occur
- ↑cerebral BF
- Uterine relaxation

Sodium nitroprusside toxicity

Cyanide ions (CN-)
- Major risk - toxic plasma levels >8ug/ml
- Free CN- ions can bind cytochrome oxidase -> uncoupling of oxidative phosphorylation -> impaired aerobic metabolism -> tissues unable to utilise O2 - hypoxia and lactic acidosis with ↑PvO2

MetHb + CN-
- Cyano-methaemoglobin (does not bind O2)

Excessive production of NO -> arterial vasodilation -> hypotension

Thiocyanate - CNS toxicity - hyperreflexia, confusion, seizure, coma

Signs
- Tachyphylaxis
- Hypotension
- Tachycardia
- Arrhythmias
- Hyperventilation
- Sweating
- Metabolic acidosis

Management
- Stop infusion
- Supplement O2
- Dicobalt edetate (chelate CN- ions)
- Sodium thiosulphate (converts CN- to thiocyanate)
- Nitrates - convert oxyHb to metHb, metHb has higher affinity to CN- than cytochrome oxidase
- Methylene blue - reducing agent, reduces metHb to Hb
- Vit B12 - forms cyanocobalamin

Question 43

GTN

Answer 43

Organic nitrate - ester of nitric acid
Clinical uses - angina, LV failure secondary to MI, peri-op BP control
Dose - 300-600mcg tablets, 400mcg SL spray, 10-400mcg/min IV infusion
- ISMN is a PO bioavailable form with same MoA

MoA
- Prodrug rapidly metabolised to NO
- NO -> ↑cGMP -> ↓Ca

PK
- A - rapid absorption from SL mucosa and GIT. Minimal PO bioavailability, extensive first pass metabolism
- D - peak effect 2mins IV, 15-30mins mucosal
- M - rapid hepatic and RBC hydrolysis to glyceryl dinitrate then nitrite then NO
- E - 80% excreted in urine. T1/2 1-3mins

CVS
- Venodilation
=> ↓VR + preload
=> ↓LVEDP + wall tension
- Arterial vasodilation at higher doses (<venodilation)
=> ↑coronary BF - redistributes flow to subendocardium, auto regulation maintained, attenuates coronary vasospasm
=> ↑cerebral BF + ICP -> headaceh
=> ↓SVR at high doses
- ↓myocardial O2 consumption - due to ↓preload and afterload
=> Primary mechanism of relieving angina, also alleviated coronary vasospasm
- Reflex tachycardia
- ↑CO in failing heart

RS
- Bronchodilation
- ↓PVR
- ↓HPV -> ↑shunt -> ↓PaO2

Other
- ↓uterine smooth muscle tone - tocolytic
- Relaxation of GIT sphincters
- Inhibit plt aggregation
- MetHb after prolonged use
- Cerebral vasodilation -> headache
- Tolerance - depletion of sulfhydryl groups in vascular SM

Question 44

Pregnancy

Answer 44

Hydralazine, labetalol - Low maternal:fetus ratio despite lipid solubility
a-methyldopa, prazosin, nifedipine

Avoid
- ACEi/ARB - teratogenic 1st trimester, later cause fetal growth restriction and oligohydramnios, incr still birth, renal failure
- DHP (CCBs) - 1str trimester teratogens
- Diuretics - reduce normal plasma volume expansion of pregnancy, electrolyte derangement
- B-blocker without ISA - ↓uterine blood flow, atenolol causes FGR
- GTN, nitroprusside (risk of CN toxicity and MetHb in foetus)

Question 45

Myocardial supply + demand + MI drugs

Answer 45

Demand = 30ml/min (directly proportional to HR, contractility, wall tension)

Supply = 250ml/min (5% CO), O2 content of blood (Hb, SaO2), coronary flow

Myocardial O2 extraction
- 60% (very high, near max)
- O2 supply can only be incr by incr flow

Drugs used to manage myocardial ischaemia/ infarction:

Nitrates
- Venodilation -> ↓myocardial O2 demand (↓preload, ↓LVEDP + wall tension)
- ↑O2 supply - coronary vasodilation and flow

BB
- ↑O2 supply - negative chronotropic effect ↑LV O2 delivery
- ↓demand - negative inotropic effect

CCB
- ↑supply - arterial vasodilation ↑Coronary BF
- ↓demand - vasodilation ↓afterload and wall tension, negative inotropic effect

ACEi/ARB
- ↑supply - ↑CBF by vasodialtion
- ↓demand - arterial vasodilation ↓afterload and wall tension, venous vasodilation ↓VR/ preload
- Activation of LDL receptors - ↓plasma LDL - plaque stabilisation

Anti-platelets, anticoagulants + fibrinolytic

Question 46

Drugs in acute or chronic cardiac failure

Answer 46

HFrEF
- Sx with or without signs of HF
- AND LVEF <50%

HFpEF
- Sx with or without signs of HF
- AND LVEF >50%
- AND objective evidence of relevant structural heart disease (LV hypertrophy, LA enlargement) and/or diastolic dysfunction with high filling pressures

Sympathomimetics
- Used for incr contractility in acute failure, i.e dobutamine

PDEi
- Inodilators (milrinone) useful for short term management of CCG
- Incr mortality with long term use

Digoxin
- Used for positive inotropy with negative chronotropy
- Improves supply/ demand balance

Diuretics
- Remove volume and ↓prelod
- Spironolactone ↓mortality from chronic CCF
- Frusemide agent of choice

ACEi
- ↓afterload and positive effect on cardiac remodelling

Nitrates
- ↓preload

B-blockers
- Improve mortality
- Prevent downregulation/ desensitisation of adrenergic receptors from chronic high sympathetic stimulus
- Carvedilol - non selective B and a1 blocker improves mortality

Neprilysin inhibitor
- Sacubitril
- Incr bradykinin, natriuretic peptides
- ↓Na+, H2O retention
- ↓remodelling

Question 47

Thiazides

Answer 47

e.g hydrochlorothiazide, chlorthalidone

Moderately potent
Site of action - early segment of DCT

MoA
- Block Na/Cl co-transporter in early segment of DCT
- ↓Na + Cl reabsorption
- ↑H2O excretion

CVS
- ↓BP by ↓plasma volume
- Arterial vasodilation -> ↓SVR

Renal/ electrolytes
- ↓RBF -> may ↓GFR
- ↓K+ - more Na reaches CD -> ↑Na/K exchange by Na/K ATPase in principal cells -> ↑K+ in CD -> ↑exchange of K for H by K/H pump in type A intercalated cells -> loss of H -> hypokalaemic, hypochloraemic metabolic alkalosis
- ↓Na+
- ↓Cl-
- ↓Mg2+
- ↑Ca
- Hyperuricaemia - uric acid competes with thiazides for the same secreting mechanism, ↓uric acid excretion
- ↑BSL - ↓insulin -> ↓glycogenesis, ↑glycogenolysis

Other
- ↑plasma cholesterol and triglyceride levels
- Blood dyscrasia

Question 48

Diuretics

Answer 48

• Thiazides - hydrochlorthiazide
• Loop - frusemide
• K-sparing - amiloride
• Aldosterone antagonist - spironolactone
• Osmotic diuretics - mannitol
• Carbonic anhydrase inhibitor - acetazolamide

Question 49

Loop diuretics/ Frusemide

Answer 49

e.g Frusemide, bumetanide

Potent diuresis
Site of action - thick ascending LoH

MoA
- Block Na/K/2Cl cotransporter in thick ascending LoH -> ↓Na + Cl reabsorption -> impaired counter current multiplier mechanism -> ↓generation of hypertonic medulla -> ↓absorption of H2O in CD -> hypotonic/ isotonic urine produced
- ↓K+ reabsorption
- Interferes with tubuloglomerular feedback - also Na/K/2Cl co-transporter

Frusemide
- Sulphonamide derivative
- Clear solution must be protected from light

PK
- A - PO bioavailability 65%, starts a few mins post IV admin, lasts 2hrs
- D - highly protein bound to albumin
- M - renal to a glucuronide
- E - 80% excreted unchanged in urine, T1/2 45-90mins

CVS
- ↓BP - ↓plasma volume (BP does not ↓ if fluid overloaded), arterial vasodilation -> ↓SVR (unclear mechanism)

Renal/ electrolytes
- ↑RBF (cf. thiazides)
- ↓K+, ↓Na+, ↓Cl-
- ↓Ca2+ (cf thiazides)
- Hyperuricaemia - ↓uric acid excretion
- ↓Renal O2 consumption - may be protective in iscahemia

Other
- ↑BSL -> ↓insulin -> ↓glycogenesis, ↑glycogenolysis
- ↑ cholesterol + triglycerides
- Metabolic alkalosis - ↑H+ excretion in distal tubules
- Deafness - esp if co-administered with aminoglycoside
- ↓cAMP in presynaptic neutron potentiating NMB

Question 50

Potassium sparing

Answer 50

E.g Amiloride

Weak potency
Site of action - DCT + CD

MoA
- Directly block Na/K exchanger
=> ↓Na reabsorption -> ↑diuresis
=> ↓K secretion -> ↑K+

PK
- Not metabolised by liver
- 50% excreted unchanged by kidneys, 40% in faeces

Question 51

Aldosterone antagonist

Answer 51

E.g spironolactone

Weak potency
Site of action - CCD

MoA
- Intracellular aldosterone receptor antagonist
=> ↓Na + H2O reabsorption -> ↑diuresis
=> ↓K secretion -> hyperkalaemia
=> Antagonism of the effect of aldosterone on arteriolar SM -> ↓BP

Spironolactone
PK
- Partially absorbed ~65%
- Undergoes enterohepatic recirculation
- T1/2 1.6hrs

CVS
- Antagonism of aldosterone effect on vascular SM -> ↓SVR + ↓BP

Other
- Cross reactivity with other receptors - androgen receptor antagonist (e.g gynaecomastia)
- Progesterone receptor agonist -> menstrual irregularities

Aldosterone
- Acts in renal CCD to ↑Na reabsorption, K+ secretion by principle cells, and H+ secretion by type A cells

Question 52

Osmotic diuretic/ Mannitol

Answer 52

Monosaccharide derived from mannose
Clinical uses - ↓ICP, diuresis post renal transplant, bowel prep
10% and 20% solution (1100mOsm/L for 20%)

MoA
- Two phases
=> Volume expansion (VE) - ↑plasma volume, ↑plasma osmolality -> contraction of ICF
=> Volume contraction (VC) - osmotic diuresis, ↓plasma volume

• Volume expansion
  => Hypertonic compared to plasma
  => ↑plasma osmolality - movement of fluid from interstitial to intracellular spaces => ↑plasma volume + ↓intracellular volume
  => Activation of osmotic receptors -> ↑ADH secretion and thirst -> early volume retention
• Volume contraction
  => Freely filtered but not reabsorbed or secreted
  => ↑osmolarity of the tubular fluid/filtrate
  => ↓passive water reabsorption down Na gradient - impairs passive reabsorption of solutes requiring concentration gradient from water reabsorption (glucose, etc), water loss in excess of electrolytes
  => ↑renal plasma renal flow rate - washes out medullary conc gradient -> ↓ability to produce concentrated urine
  => ↑urine flow rate - osmotic drag
• Diuresis
  => Osmotic effect - diuresis limited by compensatory ↑ADH. Hyponatraemia and hypokalaemia (↑Na/K exchange in distal nephron due to high flow rate). Urea may ↑
  => ↑RBF
  => ↓Renin secretion

PK
- D - does not freely cross BBB, does not cross cell membranes (large molecules). Acts within a few mins and last 1-4hrs. Biphasic distribution to plasma and ECF
- M - not metabolised
- E - excreted unchanged in urine. T1/2 70mins

CNS
- ↓CSF/ ICP
- ↓rate of CSF formation - ↑plasma osmolarity ↓ultra filtrate
- Withdraws brain ECF across the BBB into the plasma - if BBB disrupted crosses and is thus ineffective
- Preserved CBF in pt with intact autoregulation

CVS
- ↑CO + BP initially in VE phase
- Volume contraction -> ↓preload and ↓CO, can lead to impaired perfusion if severe

Adverse
- Circulatory overload - pulmonary oedema (esp in CCF), compensatory ↑ANP: ↑RA stretch -> ↑release -> diuresis, natriuresis
- Rebound ↑ICP - production of idiogenic osmoles, hence ↑risk of cerebral oedema
- Allergy rare
- Irritant to tissues and veins
- Possible toxic effects on DCT + CD
- ↑osmolarity >320mOsm/L if >3g/kg/day given
- Dehydration and hypovolaemia - diuresis and volume loss
- Electrolyte disturbances

Question 53

Carbonic anhydrase inhibitor

Answer 53

e.g acetazolamide

Weak potency
Site of action - PCT

MoA
- Carbonic anhydrase catalyses
CO2 + H20 <=> H2CO3 <=> H+ + HCO3-
- Non-competitive inhibition of carbonic anhydrase
=> ↓HCO3 reabsorption + ↓H secretion ->
=> Metabolic acidosis
=> Alkaline urine
=> ↓ability to exchange Na for K -> ↓Na reabsorption -> ↑diuresis

Question 54

Vaughan-Williams Classification of Anti-arrhythmics

Answer 54

Class Ia
- Na+ channel blockade -> mod reduction in slope of phase 0, ↑duration of refractory period, ↑duration of AP
- Site of action - atria, ventricles, accessory pathways
- E.g quinidine, procainamide
- Uses - ventricular arrhythmia, prevention of pAF, maintain SR post conversion of AF/WPW
- Advers - QT prolongation

Class Ib
- Na+ channel blockade -> small reduction in slope of phase 0, ↓duration of refractory period, ↓duration of AP
- Site of action ventricles
- E.g lignocaine, phenytoin
- Uses - VF/VT (lignocaine)

Class Ic
- Na+ channel blockade -> pronounced reduction in the slope of phase 0, nil effect on refractory period, nil effect on duration of AP
- Site of action - atria, ventricles, accessory pathways
- E.g flecainide, propafenone
- Uses - prevention of pAF, tachyarrhythmias with abnormal conduction, avoid in structural heart disease/ MI - can cause HF

Class II
- B-adrenoceptor -> no change of phase 0, ↑duration of refractory period, ↑duration of AP
- Site of action - SAN, AVN
- E.g propranolol, atenolol, esmolol
- Uses - rate control, reduce MI mortality

Class III
- K+ channel blockade (Ik1) -> no change of phase 0, prolonged repolarisation phase 3, ↑↑duration of the refractory period, ↑duration of AP
- Site of action - atria, ventricles, accessory pathways
- E.g amiodarone, bretylium, ibutilide, sotalol (both class II + III)
- Uses - WPW, VT/VF, maintain SR post AF conversion
- Adverse - prolong QT

Class IV
- L-type Ca channel blockade -> nil change of phase 0, ↓duration of plateau phase 2, ↓duration of AP
- Site of action - AVN
- E.g verapamil, diltiazem
- Uses - prevention of recurrent SVT, rate reduction in AF

Other
- Adenosine - activates adenosine receptors
- Digoxin - Na pump inhibitor
- Mg - CCB

Question 55

Flecainide

Answer 55

Amide LA
Class IIc antiarrhythmic - Na channel blocker -> ↓rate of max depolarisation, pronounced reduction in slope 0, nil change to refractory period, nil change to duration of AP

Uses - prevention pAF, tachyarrhythmia with abnormal conduction (WPW), avoid in structural heart disease/ MI - can cause HF

PK
- A - rapid PO absorption, 90% bioavailability
- M - hepatic
- E - Urine, dose reduction in renal/ hepatic impairment

CVS
- Well tolerated, min BP + HR effects
- Negative inotrope potential

Other
- Visual disturbances
- Liver impairment
- Nausea, headache

Drug interaction
- Incr Cp of digoxin
- Hypokalaemia reduced effect

Question 56

Amiodarone

Answer 56

Resembles thyroxine
Clinical uses - SVT, VT, WPW, cardiac arrest with shockable rhythm, rate control in AF
Dose - 300mg push in arrest, 150-300mg load, 15mg/kg/day subsequently, therapeutic level 0.1mcg/ml

MoA - Class III anti arrhythmic
- K+ channel blockade - ↓slow outward K+ current (at higher doses blocks Na + Ca inward currents), prolonged repolarisation phase 3, ↑↑duration of refractory period, ↑duration of AP
- Partial antagonist of a- and b- agonists by reducing receptor number or inhibiting coupling of receptors to adenyl cyclase
- Class Ia, II and IV activity in addition

PK
- A - variable PO bioavailability (20-80%)
- D - 95% protein bound, VD up to 70L/kg - accumulated in muscles and fat (long duration of action + T1/2), very large Vd due to tissue accumulation (requires prolonged loading). IV onset 5mins, IV duration 30mins for bolus. High lipid solubility.
- M - extensive hepatic metabolic -> active metabolite (anti arrhythmic properties)
- E - Predominantly bile, but also through lacrimal glands and skin. T/12 15-140days

CVS
- Slows SR, prolongs AV conduction - prolongs AP and RP (primarily K channel blockade), no change to phase 0, prolonged repolarisation phase 3
- Prolonged QT interval
- Rapid infusion -> bradycardia + hypotension (B and a blockade -> vasodilation + ↓CO)

RS
- Pulm fibrosis/ ILD (risk factors - prolonged therapy, high cumulative dose, ↑age, pre-existing pulm disease, ↑FiO2)

Other
- Hypothyroidism&raquo_space; hyperthyroidism (inhibit T3 production)
- Hepatitis
- GI upset
- Corneal micro-deposits
- Peripheral neuropathies
- Photosensitivity
- Blue-grey discolouration of skin

Drug interaction
- Drugs that prolong QTc (e.g droperidol, TCA, phenothiazines)
- Drugs that ↓AVN conductivity (e.g B-blockers, CCB)
- Potentiates effect of highly protein bound drugs by displacement (e.g warfarin, phenytoin, digoxin)

Question 57

Verapamil

Answer 57

Synthetic papaverine derivative
Calcium channel blocker
Clinical uses - paroxysmal SVT, AF/ Aflutter rate control

MoA
- Class IV antiarrhythmic
- Competitive antagonist of L-type Ca channels
- ↓Ca influx into cardiac and vascular SM
- ↓slow Ca depolarisation
- ↓HR - slows conduction through SAN + AVN
- No change to phase 0, ↓duration of plateau phase 2 + AP

PK
- A - complete PO absorption, 20% bioavailability due to extensive first pass metabolism
- D - 90% protein bound
- M - hepatic, metabolites have some activity
- E - 70% in urine, T1/2 5hrs

CVS
- ↓AVN conduction + HR
- ↓SVR
- Potent coronary vasodilator
- Negative dromotropic and inotropic effects enhanced by acidosis

Adverse
- Flushing, dizziness
- Heart block
- HF if impaired LV function
- VT/ VF in WPW

Drug interactions
- Synergy with volatiles on negative isotropy and conduction (dromotropy)

Question 58

Digoxin

Answer 58

• Glycoside - extracted from leaves of digitalis
• Steroid cyclopentanopenanthrene nucleus with
  => Glycone portion (inactive) -> sugar that fixes drug to cardiac muscle
  => Aglycone portion (active) -> exerts drugs activity
• Clinical uses - AF/ Aflutter, cardiac failure
• Doses - loading 10-20mcg/kg Q6hrly, maintenance 10-20mcg/kg/day in divide doses

MoA
- Direct action
=> Inhibits cardiac Na/K ATPase -> ↑intracellular Na, ↓K -> ↓Ca extrusion by Na/Ca exchanger due to ↓Na gradient -> ↑intracellular Ca -> positive inotropic effect
=> ↓intracellular K hyperpolarises cell and slows AV conduction and automaticity of pacemaker cells -> ↑AVN refractory period

• Indirect action
  => ↑release of Ach at cardiac MAChR - vagotonic
  => ↓SAN automaticity and AVN conductivity
  => Negative chronotropic effect - rate control

PK
- A - variable PO absorption, 60-80% bioavailability
- D - 25% protein bound, VD 5-10L/kg (very large), peak effect at 2hrs
- M - min hepatic metabolism
- E - renal, T1/2 35hrs, up to 5days with renal impairment

ECG changes
- Therapeutic - down sloping ST depression, QT shortening, flattened, inverted or biphasic T-waves, slight prolongation in PR, presence of U waves

Digoxin Toxicity
- Low therapeutic index
=> Therapeutic plasma level 1-2ng/ml
=> Toxic plasma levels >2.5ng/ml
- Incr automaticity, Decr AVN conduction, sinus brady, PVCs, AF, AV block, VT

Risk factors
- Hypokalaemia
- Hypercalcaemia
- Acid base disturbances
- Renal failure

Cardiac toxic effects
- Premature ventricular contraction
- AV block
- Junctional rhythm
- Prolonged PR interval
- Ventricular arrhythmia

ECG
- Incr automaticity (SVT and atrial extrasystoles)
- ↓AVN conduction
- Shortened PR interval - junctional rhythm
- Frequent PVCs
- Sinus bradycardia
- AF with escape rhythm/ slow AF
- AV block
- VT

Non-cardiac
- Anorexia
- N+V
- Diarrhoea
- Visual disturbances
- Lethargy, headache, confusion, coma

Tx
- Gastric lavage
- Correct exacerbating factors
- Bradycardia - atropine, pacing
- Ventricular arrhythmias - phenytoin, lignocaine
- Digoxin specific Fab (Digibind) - plasma level >20ng/mL, forms inactive digoxin-Fab complex -> ceases its therapeutic effect -> renally excreted

Question 59

Adenosine

Answer 59

• Endogenous purine nucleoside
• Present in all cells
• Uses - SVT due to re-entry circuits involving AVN
• Contraindications - asthma, 2nd/3rd degree AV block, sick sinus syndrome
• Dose - 6mg bolus then 12mg bolus if nil effect

MoA
- Action on SAN and AVN via adenosine A1 receptors
=> GiPCR -> ↓adenyl cyclase -> ↓cAMP -> opens K+ channels -> ↑K+ efflux -> hyperpolarisation -> ↓AVN conduction and prolongs refractory period -> negative chronotropic effect

PK
- Rapid metabolism by adenosine deaminase or phosphorylation to AMP
=> Vessel wall + RBCs
=> Incr plasma urate
- T1/2 <10s
- Antagonised by methylxanthines - inhibit A1R
- Potentiated by dipyridamole -> inhibit adenosine uptake

CVS
- Negative chronotropic effect
- Incr myocardial blood flow due to coronary vasodilation
- ↓PVR via endothelial A2 receptors

Adverse (short-lived)
- Feeling of impending doom
- Bronchospasm, dyspnoea
- Nausea
- May cause VF if underlying AF and accessory pathway

Question 60

Magnesium sulphate (MgSO4)

Answer 60

• 1g = 4mmol
• Uses - Torsades, refractory VT, tocolysis, pre-eclampsia, severe asthma, ↓Mg, ↓HTN response to intubation

MoA
- Cofactor in >300 enzymes including Na/K ATPase and oxidative phosphorylation
- Membrane stabilising effect
- Physiological antagonist of L-type Ca channels -> ↓SAN automaticity and ↓AVN conduction
- NMDA antagonist
- Ca antagonism -> SM relaxation

PK
- Normal = 0.7-1.1 mmol/L
- Therapeutic = 2-3.5
- Drowsiness = 4
- Absent patella reflex = 5
- Heart block + resp paralysis = 7.5
- Cardiac arrest >12
- Very high TI

Effects
- Vasodilation
- Antiarrhythmic
- Bronchodilation
- Tocolysis
- Sedation
- ↓Platelet aggregation
- Prolongs effect of NDMR

Question 61

Structure Function Sympathomimetics

Answer 61

Catecholamines:

A catechol ring
- A benzene ring with two hydroxyl groups in the 3 and 4 position.
- Losing one hydroxyl group
Increases lipid solubility and decreases the potency 10-fold
Prevents metabolism by COMT, prolonging duration of action
- Losing both hydroxyl groups decreases the potency 100-fold
- Changing the hydroxyl groups to the 3 and 5 position increases beta-2 selectivity when there is also a large substitution present on the amine group

An ethylamine tail
-Beta carbon
The first carbon.
Adding a hydroxyl group decreases lipid solubility and CNS penetration
Adding any group increases alpha and beta selectivity
-Alpha carbon
The second carbon.
Adding a group prevents metabolism by MAO, prolonging duration of action
Methylation increases indirect activity
- Amine group
The terminal nitrogen.
Addition of a methyl group generally increases beta selectivity
As the chain length increases, so does the beta selectivity.

Question 62

CVP Waveform

Answer 62

A wave (atrium)
- RA contraction
- Correlates with P-wave on ECG
- Disappears with AF

C wave (cusp)
- Cusp of TV protruding back through atrium, as RV begins to contract
- Correlates with the end of QRS complex

X descent
- Movement of the RV, which descends as it contracts
- Downward movement decreases the pressure in the RA. At this stage there is also diastolic relaxation, which further decreases RAP
- Happens before T-wave

V wave
- As blood fills the RA, hits TV and this is the back pressure wave
- Happens after the T-wave
- Also gives an impression of tricuspid competence
- Huge V wave suggests TR, as it represents blood flowing back out of the contracting RV; in this situation the V wave would be the most prominent wave and would reach RV systolic pressure (~30mmHg)

Y descent
- Pressure decrease caused by the TV opening in early ventricular diastole
- Happens before P-wave
- Loss of y-descent suggests tamponade; it means there is restriction to RV filling